Pharmaceutical composition containing γ-hydroxybutyric acid or its lactone in the treatment of drug dependence and nutritional disorders

ABSTRACT

γ-Hydroxybutyric acid and its physiologically equivalent forms are useful in the treatment of the syndromes of abstinence, craving and dependence on drugs, drugs of abuse, psychotropics, stupefacient and/or psychoactive substances, nicotine, or nutritional disorders.

This application is the National stage of PCT/EP92/01409, filed 23 Jun.1992.

The present invention relates to pharmaceutical compositions havingtherapeutic effects on abstinence, on craving (the intense andcompulsive desire for a substance), and on dependence on drugs, drugs ofabuse, psychotropics, stupefacient and/or psychoactive substances,nicotine and also on nutritional disorders (in particular bulimia,obesity and anorexia) , such compositions being characterised in thatthey contain, as the active principle, γ-hydroxybutyric acid (GHB), orsalts thereof with pharmaceutically acceptable cations, or thecorresponding lactone.

The invention further relates to the use of γ-hydroxybutyric acid or ofits physiologically equivalent forms for the preparation of a medicamentwhich is useful in the treatment of the withdrawal syndrome induced bydrugs, drugs of abuse, psychotropics, stupefacient and/or psychoactivesubstances and nicotine.

The relevant salts of GHB include, for example, alkali metal (e.g.sodium or potassium) salts, alkaline earth metal (e.g. calcium ormagnesium) salts, ammonium salts, salts of pharmaceutically acceptablebases (ethanolamine, diethanolamine, piperidine, piperazine and thelike) , salts of basic amino acids (lysine, ornithine, citrulline) etc.

GHB, various salts thereof and its lactone have been known for decades.The acid is a normal constituent of the central nervous system (CNS) ofmammals, with the highest concentration in the hypothalamus and in thebasal ganglia (c % 1.78 nM/g and 4.1 nM/g in rats and in guinea pigs,respectively).

The almost universal prevalence of binding sites for GHB in the CNSmakes it probable that such a compound acts as a neurotransmitter and asneuro-modulator, rather than as incidental metabolite of γ-aminobutyricacid (GABA). The use of GHB in clinical practice has been known for manyyears for general anaesthetic and narcoleptic purposes, with prevailingutilisation by way of intravenous administration (see Anesth. Analg.(Cleve), 41, 721-726, 1962; Science 143, 1045-1047, 1964;Electroencephalogr. Clin. Neurophysiol., 22, 558-562, 1967; Sleep, 9,285-289, 1986). More recently, the clinical use of GHB for ethyl alcoholanti-abstinence purposes has been described (see The Lancet, 2,787-789,1989).

It has now surprisingly been found that γ-hydroxybutyric acid andphysiologically equivalent forms can advantageously be utilised for thetreatment of the so-called withdrawal syndrome from drugs, drugs ofabuse, psychotropics, stupefacient and/or psychoactive substances andfrom nicotine; in particular, drugs such as narcotics, opiates, cocaine,cannabinoids or psychoactive substances such as benzodiazepines,psychostimulants, amphetamines, nicotine and their derivatives or thelike. The use of γ-hydroxybutyric acid has also proved to be effectivein the treatment of nutritional disorders such as bulimia, obesity andanorexia.

The withdrawal syndromes, dependences on drugs, drugs of abuse,psychotropics, stupefacient and/or psychoactive substances andnutritional disorders have as their common denominator the manifestationof so-called "craving" which can be defined as an intense and compulsivedesire for a given substance or a given food.

γ-Hydroxybutyric acid has proved to be particularly active in inhibitingthe onset of such-symptoms, as it has been possible to demonstrate onthe basis of clinical experiments on 23 subjects meeting the diagnosticcriteria of opiate dependence and on 3 patients affected by nutritionaldisorders (one case of anorexia, one of bulimia and one of obesity).

Table 1 shows the characteristics of the groups of subjects employed, inaccordance with a "double blind" scheme, for the study of the activityof GHB in the treatment of the opiate withdrawal syndrome.

Eleven subjects were treated with GHB, including six who had used heroinin the last 24 hours (5 M, 1 F) and 5 undergoing methadone treatment (4M, 1 F).

The control group consisted of 12 patients, 7 who used heroin (6 M, 1 F)and 5 undergoing therapy with methadone (3 M, 2 F). The two groups werehomogeneous with regard to age, sex, duration and physical condition(Table 1).

                  TABLE 1                                                         ______________________________________                                        Characteristics of the groups                                                                   GHB      PLACEBO                                            No.               11       12                                                 ______________________________________                                        M                 9 (81%)  9                                                  Age (years)       22 ± 2.3                                                                            21.6 ± 3                                        Duration Tx (years)                                                                              4 ± 1.5                                                                             3.5 ± 1.7                                      Anti-HIV antibody 3 (27%)  4 (33%)                                            positivity                                                                    Serious socioenviron-                                                                           6 (54%)  8 (66%)                                            mental problems                                                               ______________________________________                                    

In addition to the heroin abuse, the patients showed the simultaneoususe of benzodiazepine and/or cocaine, cannabinoids, amphetamine-typepsychostimulants or nicotine.

The GHB group was treated by the oral route in 6 administrations (1.5mg/kg/weight/day).

The start of the treatment was decided on the basis of the onset of anabstinence symptomatology and was continued for 4 days in the case ofthe patients who had used heroin in the preceding 24 hours; treatmentwas continued for 8 days in the case of the patients who had usedmethadone.

If, within 1 hour, there was no manifestation of a regression of thesymptomatology of the abstinence syndrome, the patient was referred forconventional anti-abstinence treatment.

On the 4th and 8th day respectively, the patients were subjected to analtrexone induction by means of the administration of 0.4 mg ofnaloxone by the intravenous route, and then of 10 mg of naltrexone onthe first day, 20 mg on the second day, 50 mg on the third and, then,were referred for a multimode treatment.

During hospitalisation, no provision was made for the intake of anyother drug, other than those indicated.

The GHB treated subjects showed, at 15' from the first administration, areduction in the symptomatology, which subsequently declined so as todisappear within 30'. The patients reported subjective wellbeing. In onecase, a report was given of a feeling of slight dizziness, whichdisappeared after 30' without involving departure from the trial.

The absence of withdrawal symptoms and the feeling of wellbeingcontinued throughout the duration of the trial (Table 2).

In all the subjects, with the exception of one case, it was possible onthe fourth day (heroin) or on the eighth day (methadone) to administer0.4 mg of naloxone via the intravenous route and then 10 mg ofnaltrexone via the oral route, without the appearance of undesiredeffects.

The naltrexone induction was completed on the following days;subsequently, the patients were assigned to the out-patients multimodeprogramme.

On completion of the trial, there was no evidence of the presence ofdrugs of abuse, psychotropics, stupefacient and/or psychoactivesubstances in the urine of any of the subjects of the GHB group.

No differences were noted in the results between the subjects who tookheroin and those who were on methadone treatment.

                  TABLE 2                                                         ______________________________________                                        Abstinence from opiates, assessed according to the Wang                       scale, in subjects treated with GHB and with a placebo                        (Scores from 0 to 10 - abstinence absent                                      from 10 to 20 - slight abstinence                                             from 20 to 30 - moderate abstinence)                                                       GHB      PLACEBO                                                 ______________________________________                                        on intake       10 (11-22)                                                                              10 (11-21)                                          at 30'         10 (3-5)   10 (12-25)                                          at 3 hours     10 (0-3)   15 (15-26)                                          at 12 hours    10 (0-3)   --                                                  at 24 hours    10 (0-5)   --                                                  after naloxone 10 (0-3)   --                                                  ______________________________________                                    

In the clinical study on 3 young female subjects affected by nutritiondisorders and treated using the same dosage scheme but with doses 50%less than those utilised for the subjects affected by withdrawalsyndromes, after one month from the start of the treatment a significantimprovement was noted in the general clinical conditions and in theintensity of the craving.

The compositions forming the subject of the invention may be prepared byemploying conventional excipients and techniques, such as thosedescribed in Remington's Pharmaceutical Sciences Handbook, Mack Pub.Co., New York, U.S.A.

The preferred administration route is the oral route using capsules,tablets, syrups or equivalent forms. It may be advantageous to employadministrations via the parenteral and/or intravenous route anddelayed-release forms, for the purpose of reducing the frequency ofadministration imposed by the pharmacokinetics of the active principle.

The average daily dose will depend on a number of factors, such as theseriousness of the condition to be treated, as we 11 as the weight, sexand age of the patient but, in general, this dose will be within therange 0.5 to 10 mg/kg/day, preferably between 1 and 2.5 mg/kg/day.

We claim:
 1. The method of treatment of a human subject affected bynutritional disorders which consists of administering to said humansubject a composition containing 0.5-10 mgs/kg/day of body weight ofsaid human subject of γ-hydroxybutyric acid, a salt thereof or thelactone thereof.
 2. The method according to claim 1 wherein saidcomposition contains 1-2.5 mgs/kg/day of γ-hydroxybutyric acid, a saltor the lactone thereof.
 3. The method according to claim 1 wherein saidcomposition is administered orally, parenterally or intravenously. 4.The method according to claim 1 wherein said nutritional disorder isbulimia or anorexia.
 5. The method according to claim 3 wherein saidcomposition is administered in the form of a delayed releaseformulation.
 6. The method of treatment of a human subject affected bywithdrawal symptoms from the use of a narcotic, an opiate, cocaine,benzodiazepine, a psychostimulant, amphetamine or nicotine or mixturesthereof which consists of administering to said human subject acomposition containing 1.5 mg/kg/weight/day of γ-hydroxybutyric acid, asalt thereof or the lactone thereof.
 7. The method according to claim 6wherein said composition is administered orally, parenterally orintravenously.
 8. The claim according to claim 7 wherein saidcomposition is administered in the form of a delayed releaseformulation.
 9. The method according to claim 6 wherein said humansubject is affected by the simultaneous use of benzodiazepine, cocaine,heroin, an amphetamine-type psychostimulant and nicotine.